CRISPR/Cas9-Induced (CTG⋅CAG)_n Repeat Instability in the Myotonic Dystrophy Type 1 Locus: Implications for Therapeutic Genome Editing.

ABSTRACT: Myotonic dystrophy type 1 (DM1) is caused by (CTG⋅CAG)_n-repeat expansion within the DMPK gene and thought to be mediated by a toxic RNA gain of function. Current attempts to develop therapy for this disease mainly aim at destroying or blocking abnormal properties of mutant DMPK (CUG)n RNA. Here, we explored a DNA-directed strategy and demonstrate that single clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-cleavage in either its 5' or 3' unique flank promotes uncontrollable deletion of large segments from the expanded trinucleotide repeat, rather than formation of short indels usually seen after double-strand break repair. Complete and precise excision of the repeat tract from normal and large expanded DMPK alleles in myoblasts from unaffected individuals,

SUBMITTER: van Agtmaal EL 

PROVIDER: S-EPMC5363205 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature